Bioadhesion is the characteristic of certain natural and synthetic polymers of binding to various biological tissues. Of particular interest are polymers which bind to the mucous lining that covers the surface of many tissues which communicate directly or indirectly with the external environment, such as the gut, respiratory tract, reproductive organs, and cornea. Mucus binding polymers may be referred to as mucoadhesive.
Several bioadhesive, and specifically mucoadhesive, polymers are known. The chemical properties of the main mucoadhesive polymers are summarized as follows:
a. strong H-bonding groups (--OH, --COOH) in relatively high concentration; PA1 b. strong anionic charges; PA1 c. sufficient flexibility of polymer backbone to penetrate the mucus network or tissue crevices; PA1 d. surface tension characteristics suitable for wetting mucus and mucosal tissue surfaces; and PA1 e. high molecular weight.
Bioadhesive polymers currently used in pharmaceutical preparations include: carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), polyacrylic and polymethacrylic acid and their derivatives, pectin, alginic acid, chitosan, polyvinylpyrrolidone, hyaluronic acid, and polyvinylalcohol. The most frequently used polymer is Carbopol (Carbomer), which is a high molecular weight polyacrylic acid polymer. It is used in many formulations for bioadhesive drug delivery systems, as a suspending agent, as a tablet coating, and in ocular suspensions.
Carbopol forms thixotropic mixtures with water at pH above 6.5 and at concentrations as low as 0.25-0.3% in water. The (gel-forming properties of Carbopol strongly depend on salt concentration and ionic strength of the formulation. The drug delivery enhancing effect of Carbopol on coated tablets may be due to both the polymer-mucus interaction and the prolongation of residence time due to increased viscosity.
Many workers have investigated the effect of pH on the interaction of polyacrylic acid with mucus, noting that the adhesion of acrylic-based polymers to mucous membrane is greater at pH&lt;6. Protonation of the carboxyl groups (pKa 4.75) permits H-bonding between the polymer and the mucin network, resulting in enhanced retention of the polymer in contact with a mucosal surface.
Several reports of liposome suspensions containing bioadhesive polymers have been published recently. Interaction between mucoadhesive polymers and phospholipid vesicles has, in turn, resulted in the prolonged corneal residence of those vesicles.
The biological effects of incorporating bioadhesive polymers into drug formulations can be tested by various methods, such as increased retention time while in the eye or increased effective drug concentration. One of the models for bioadhesion testing involves interaction of the drug delivery system under investigation with ocular surfaces such as conjunctiva or cornea. A new ocular formulation of the beta-blocker betaxolol, "Betoptic S," contains the drug absorbed on micropowdered cation exchange resin suspended in aqueous solution with Carbopol. Carbopol in this formulation is a suspending and viscosity regulating agent.
Corneal retention of Carbopol coated phosphatidylcholine liposomes is significantly greater compared with uncoated liposomes, especially at pH 5.0. In a model study, the miotic agent tropicamide was employed in a liposomal formulation; Davies et al., J. Pharm. Res. (1992) 9:1137-1144. The pH-dependent lecithin-in-polyacrylic binding, followed by complex formation, was described for three liposome preparations. It was found that every phosphatidylcholine vesicle was coated with a swollen gel layer, and the mean particle size increased from 260 to 1300 nm. Such modification decreased the rate of drug release from liposomes and increased retention time of liposomes in the eye, but no significant differences were found in activity and bioavailability between the drug in solution and in Carbopol-coated liposomes.
In EPA 0028110, polyacrylic acid derivatives are claimed as stabilizers for pharmaceutical emulsions. Carbopol in such compositions, at concentrations near the gel-point and at neutral pH, stabilizes the emulsion. Final preparations exhibited a viscosity of 66-132 centipoise, and could be autoclaved. Bioadhesive properties were not reported and would not be expected, since in all examples the emulsions were adjusted to pH 7, at which mucosal binding is minimal.
Zerbe et al., WO 93/00076, disclose a drug delivery system of microparticles having a spherical core composed of a biopolymer, preferably a protein such as albumin or gelatin, which typically has been crosslinked or denatured to maintain its structural coherency. The spherical core is suggested to be combined with a bioadhesive polymer.
Riley, U.S. Pat. No. 5,055,303, discloses a bioadherent emulsion of the water-in-hydrophobic phase type wherein the continuous hydrophobic phase is a solid fat. Bioadhesion is not attributed to a specific adherent component, but rather is apparently ascribable to the viscosity of the solid continuous phase.